There is a fundamental lack of knowledge in the modalities and principles that govern parasite-host interactions. This gap prevents the rational design of approaches to effectively disrupt interactions that will result in efficient parasite control. In the past, simple models of monomeric binding for receptor-ligand interactions have been invoked, simplifying experimental study but limiting our understanding of how interactions are truly manifested during pathogenesis. Recently, the larger view of interactions suggests that the induction of multimeric assemblies and higher order states upon binding, through oligomerization or tandem duplication of binding sites, are critical to the formation of strong interactions between the parasite and the host/vector. The identification of all multimeric contact interfaces within a complex, including interaction and oligomerization contacts, are not only fundamental to the structural understanding of interactions but also reveal additional targets for disruption as described below. We plan to comprehensively dissect the fundamental principles that drive multimeric assembly of parasite-host interactions, and that enable their efficient disruption at the molecular level. We focus on essential host-pathogen/receptor-ligand interactions required for host infection and vector transmission of the malaria parasites Plasmodium falciparum and Plasmodium vivax. Fundamental principles of this study include multimerization of interacting partners, creation of specific binding pockets, structural changes upon binding, and the role of multiple binding sites within a complex on cooperativity and avidity. The role of variable (polymorphic) and constant regions of interacting partners in engagement will also be uncovered. These fundamental principles will be uncovered by studying the structural and mechanistic basis for assembly of parasite-host interaction with well validated roles as potential vaccine candidates and/or as required for parasite viability. In FY 2019, we described a novel phenomenon of red cell clustering that enhances P. falciparum growth and protects from neutralizing antibodies (described in scientific advances). In addition, we published a review of the literature describing the structure, function and vaccine potential of blood-stage malaria parasite antigens. Our long-term goal is to elucidate the principles that enable multimeric assembly of microbe-host interactions, and to exploit these principles for preventative, therapeutic, and diagnostic purposes. The proposed research will define receptor specificity within parasite protein families and uncover fundamental principles that underlie parasite-host interactions. The identification of regions required for assembly can be exploited for the development of novel interventions and vaccines by focusing the immune response to target these regions exclusively. Finally, diagnostics that measure the immune response to functional regions will lead to better measures of protection.